Transforming Growth Factor-Beta (TGF-?) has profound immunosuppressive effects on a variety of immune cells. Natural killer (NK) cells are large granular lymphocytes that constitute a vital component of the innate immune system. NK cells produce abundant interferon gamma (IFN-?) to enhance tumor cell recognition and destruction, and to clear viral infection, including herpes simplex oncolytic viruses (OVs) in glioblastoma (GBM) treatment. Due to its complexity, TGF-? signaling has not been fully characterized. It also remains to be determined whether TGF-? itself or TGF-? signaling can be modulated to control NK cell functions in order to better control tumor progression and to enhance OV therapeutic efficacy in GBM. We hypothesize that TGF-? signaling can be further elucidated and modulated in NK cells to better understand cancer progression and enhance cancer treatment. Our goal is to investigate the molecular basis of how TGF-? suppresses NK anti-tumor activity by identifying the elements directly involved in this process, and to study the potential to increase the signaling to improve NK anti-tumor activity, but to decrease NK activity by pre-TGF-? treatment in the context of OV therapy, where NK cells limit OV expansion and therapeutic efficacy. Our proposed studies have a great potential to advance GBM treatment and/or GBM prevention and make us understand more about tumor and virus recognition and destruction. We will test our hypothesis through three Aims: 1) To determine the molecular basis of transcriptional repression of NK cell function by TGF-?; 2) Can we disrupt TGF-? signaling to increase immune responses, and, in turn, to control GBM progression in vivo? 3) To augment TGF-? signaling in NK cells to enhance OV therapy efficacy in GBM.